The present invention is directed to a process for the preparation of a stable, homogeneous extract free or nearly free, from secondary reaction products, which contains the respective desired genuine substance mixture in a complete or nearly complete form, whereby this extract is obtained from plants or parts thereof, which may be charged in a fresh and/or dried state in treated or untreated form.
This invention is also directed to a means for carrying out this process.
This invention is also directed to a stable, homogeneous extract free or nearly free, from secondary reaction products which is obtained from plants or parts thereof.
Usually plant extracts are prepared through extraction with alcohols, mixtures of water and alcohols or also only with water.
When such a plant extract shall be transferred into a viscous form, a so called spissum extract, or into a dry form, a so called siccum extract, then the present solvent or mixture of solvents must be removed partially or completely.
This is usually done under evaporation of the solvent(s) under reduced pressure and at elevated temperatures.
These processes are described in pharmacopeias, for example in xe2x80x9cDeutsches Arzneibuchxe2x80x9d (DAB) or in xe2x80x9cEuropxc3xa4isches Arzneibuchxe2x80x9d (EuAB).
When for example Chelidonium majus L. is extracted according to such a process and is then concentrated and dried, then are observed decomposition and polymerisation processes as well as a sedimentation and a flotation of the contents compounds.
As a consequence thereof the resulting product represents not an equivalent preparation with regard to the used amount of the plant, because the so obtained substance mixture does not correspond with the genuine substance mixture, dissolved from the plant.
When for example Melilotus officinalis L. Lam. em. Thuill. is extracted according to an above mentioned process and is then concentrated and dried, then is noted a loss of volatile components, such as cumarins.
As a consequence thereof also this resulting product represents not an equivalent preparation with regard to the used amount of the plant, because the so obtained substance mixture does not correspond with the genuine substance mixture, dissolved from the plant.
When for example Hypericum perforatum L. is extracted according to an above mentioned process, what is usually done in a ratio from the plant to the used solvent from 1:1 to 1:20, especially 1:10, then the hardly soluble portions, such as the dianthrones, are extracted incompletely from the plant.
As a consequence thereof also this resulting product represents not an equivalent preparation with regard to the used amount of the plant, because the so obtained substance mixture does not correspond with the from the plant extractable genuine substance mixture.
When for example Allium sativum L. is extracted according to an above mentioned process and is then concentrated and dried, then are observed during the whole process chemical and/or enzymatic reactions between one or more in the extract contained substance(s).
These reactions are nearly completely prevented with the process described in EP 0 347 493.
The product obtained according to this process has at an elevated temperature, that is a temperature of 25xc2x0 C. and more, an insufficient stability of the thiosulfinates, for example alliin.
Such products obtained according to EP 347 493 which have been storred during a longer time, for example one month, at a temperature of more than 25xc2x0 C. represent thus no longer an equivalent preparation with regard to the genuine substance mixture dissolved from the plant.
When a tanning agents and/or isoprenoides containing plant extract is transferred into an encapsulable mass according to EP 0 496 705, then at the use of polyethylene glycol sequences containing carrier materials, such as polyethylene glycols, polysorbates, are observed sedimentations, flotations, inhomogeneities and chemical reactions during or after the preparation of such masses.
It has been noted that plant extracts, which contain tanning agents and/or isoprenoides, react during the encapsulation into a gelatin capsule with the gelatin envelope, and thus may influence the elasticity of the capsule envelope and its dissolving behavior in the stomach or in the intestine.
This drawback have the products described in EP 0 464 274 A1 and EP 0 496 705.
This behavior of tanning agents is utilized for example in the preparation of leather and is known since hundreds of years.
This behavior of certain isoprenoides, especially the aldehydo derivativs of monoterpenes and sesquiterpenes, especially their reactivity with amino groups containing compounds, is also generally known and is utilized with intention for the preparation of derivatised soft gelatin capsuls with retarded dissolving behaviour; see DAB 10, comment K 20.
According to DE PS 44 34 170 the object consists therein to provide peroral applicable extracts of Hypericum perforatum L., which have a higher release ratio with regard to conventional preparations, that is a higher bioavailability of the active components in the stomach-intestine tract.
This is ostensibly reached in that the non-volatile phase of the extract is bonded to polyvinylpyrrolidine in micro disperse form and/or in the form of a solid solution.
It is asserted in DE PS 44 34 170 that the plurality of active components shall be bonded to polyvinylpyrrolidone.
This assertion is sustained on the measurement of the liberation of the dianthrones from the extract according to the prescriptions of DAB 10 V.5.4.
But according to the examples of DE PS 44 34 170 the extract is composed only of about 0.03% (0.1 mg) dianthrones and about 99.97% (289.9 mg) of not explicitely mentioned further active components, accompanying substances and polyvinylpyrrolidone.
Experimental statements for the bioavailability of the other about 99 % of the further active components and accompanying substances are not given.
Thus, no experimental proof for the above assertion is given.
The process described in DE PS 44 34 170 is up to the receipt of the fluid extract an already above mentioned known conventional process with which no complete extraction of the active components is obtained.
The polyvinylpyrrolidone is exclusively added to this fluid extract.
In EP 0 599 307 A1 is also described a conventional process for the preparation of a fluid extract of Hypericum perforatum L.
The in this fluid extract contained dianthrones are removed selectively by the addition of polyvinylpyrrolidone by means of precipitation and filtration from this fluid extract.
In the so obtained nearly dianthrone-free product are identified experimentally further active components.
Thus, there exists a contradiction betweeen the statements contained in DE PS 44 34 170 and EP 0 599 307 A1.
In JP-A-60 222 412 is described a process for the separation of insoluble substances which are contained in aqueous liquid medicaments.
These medicaments contain plant components.
According to this document crude medicament substances on the basis of plant extracts may contain insoluble micro particles which often may be separated only hardly with usual filtration methods, and which may cause turbidities and precipitations.
According to this document, it has been found that crude medicament substances extracted from some plants may form white turbidities together with polyvinylpyrrolidone.
But when before the addition of polyvinylpyrrolidone a with polyoxyethylene hardend caster-oil derivative is added, then substances aggregate and easily form precipitates, which may be separated in an easy way.
This means that according to this document such substances are previously removed which form turbidities and precipitations. The aggregate-like precipitations are not further described.
The starting material is always an already prepared plant extract.
Thus, according to this document the undesired formation of precipitates has been optimized through previous addition of a polyoxyethylene hardened caster-oil derivative, which leads to aggregate-like and thus better separatable precipitates.
It is an object of the present invention to provide extracts from plants or parts thereof and these extracts containing pharmaceutical acceptable administrative forms, whereby these extracts shall contain the respective desired genuine substance mixture in a complete or nearly complete form.
These extracts and administrative forms shall be stable and homogeneous, and shall fullfill especially the corresponding in the international ICH-guidelines contained rules.
These extracts and administrative forms shall have in contrary to conventional products a considerably reduced or no content of secondary reaction products.
These extracts and administrative forms shall be prepared by means of a simple and economical process.
It has been found quite surprisingly that the above mentioned objects are reached when during or after the extraction of the plant or a part thereof an agent A is added.
In the inventive process are used as agent A preferably protein hydrolysates and/or polyvinylpyrrolidones.
The extract of Allium sativum L. is prepared preferably up to the receipt of the fluid extract according to the process as described in EP 0 347 493.
It has been determined that the addition of an agent A, for example Kollidon K 25 (BASF), to this fluid extract, followed by the following further processing to a dry extract, results in a product, which has a significantly reduces sensitivity against elevated temperatures.
When conventional garlic preparations are stored at elevated temperatures then are observedxe2x80x94as already mentioned abovexe2x80x94already at temperatures of more than 25xc2x0 C. losses of active substances.
These losses are not observed even at a temperature of 30xc2x0 C. with an inventive garlic preparation.
This stability improvement is a big process in a twofold manner.
Thus, on one hand expenditures during transportation and at the storage are reduced, and on the other hand the safety of the medicament is increased.
It has been determined that the addition of an agent A, for example Kollidon 17 PF (BASF), to a mainly water soluble compounds containing fluid extract of Melilotus officinalis L. Lam. em. Thuill., followed by the following further processing to a dry extract, results in a product, which has a significantly increased content of cumarins.
This is explained by the fact that the normally during the evaporation of the water/ethanol mixture volatile cumarins are retained obviously through an interaction with the agent A and thus remain in the residue.
This is a big progress because it was not yet possible to concentrate aqueous/ethanolic, cumarins containing solutions without the loss of the cumarins in an economical way.
Of special meaning are inventive extracts of Melilotus, because they are much more suitable for the preparation of injectable preparations than conventional products, because they contain the desired watersoluble active compounds and no waxes, chlorophyll and further hardly watersoluble compounds/residues.
Conventional cumarins containing extracts are only available by using highly lipophilic, waterfree or nearly waterfree solvents.
Therefore, conventional extracts contain less of the desired watersoluble active compounds and in turn more for the activity and for the use troublesome and undesired compounds.
It has been determined that the addition of an agent A, for example Kollidon K 90 (BASF), to a fluid extract of Chelidonium majus L., followed by the following further processing to a dry extract, results in a product, which has a significantly increased content of alkaloids as well as a homogeneity.
This high content of alkaloids is explained by the fact, that obviously through an interaction between the alkaloids and the agent A the decomposition processes are prevented which are observed in conventionally prepared products.
The homogeneity of this inventive extract may be explained by the fact that obviously through an interaction between the agent A and the isoprenoids a polymerisation of the latter to latex and/or latex-like compounds does not take place, and thus no phase separation occurs.
Not only are conventional preparations increased with regard to the content of alkaloids, but also the homogeneity of the product is increased.
The avoidance of the decomposition of the alkaloids has a special meaning because all important chelidoniumalkaloids contain methylene dioxy groups, which during the decomposition reactions may be cleaved as formaldehyde.
It can not be excluded that in such products the decomposition products are of toxic nature.
It has been determined that the addition of an agent A, for example Gelita-Sol D (DGF Stoess) during the preparation of the fluid extract of Herba Hyperici (Hypericum perforatum L.), the amount of the extractable dianthron compounds is significantly increased.
This may be explained by the fact that the solubility product of the in mixtures of water and ethanol only hardest soluble dianthrons, obviously through interaction with the agent A, is significantly increased.
Thereby is obtained a more complete extraction of the plant, what is a progress with regard to conventional extraction processes.
A pharmaceutical preparation having a high content of dianthrones may be important for the effect at depressive emotional deterioration states, which are associated with viral illnesses, because the dianthrons have antiviral properties.